ABSTRACT
Phenolic groups are responsible for the high clearance and low oral bioavailability of the estrogen receptor alpha (ERα) clinical candidate GDC-0927. An exhaustive search for a backup molecule with improved pharmacokinetic (PK) properties identified several metabolically stable analogs, although in general at the expense of the desired potency and degradation efficiency. C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being sterically protected from glucuronide conjugation. The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency.
Subject(s)
Azetidines/pharmacology , Estrogen Receptor alpha/metabolism , Flavonoids/pharmacology , Administration, Oral , Animals , Azetidines/administration & dosage , Azetidines/metabolism , Azetidines/pharmacokinetics , Crystallography, X-Ray , Drug Discovery , Drug Stability , Flavonoids/administration & dosage , Flavonoids/metabolism , Flavonoids/pharmacokinetics , Humans , MCF-7 Cells , Microsomes, Liver/metabolism , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).
Subject(s)
Dermatitis, Atopic/genetics , Interleukin-13/metabolism , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Humans , Signal TransductionABSTRACT
A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.
Subject(s)
Cycloheptanes/chemistry , Cycloheptanes/pharmacology , Muscarinic Antagonists/administration & dosage , Muscarinic Antagonists/chemistry , Pulmonary Disease, Chronic Obstructive/drug therapy , Administration, Inhalation , Animals , Bronchoconstriction/drug effects , Cycloheptanes/pharmacokinetics , Disease Models, Animal , Guinea Pigs , Humans , Molecular Structure , Muscarinic Antagonists/pharmacokinetics , Receptors, Muscarinic/chemistry , Receptors, Muscarinic/metabolismABSTRACT
We report the optimization of a series of non-steroidal GR antagonists that led to the identification of compound 7. This compound is efficacious when dosed orally in an olanzapine-induced weight gain model in rats.
Subject(s)
Benzodiazepines/pharmacology , Drug Discovery , Receptors, Glucocorticoid/antagonists & inhibitors , Thymine/analogs & derivatives , Weight Gain/drug effects , Administration, Oral , Animals , Benzodiazepines/administration & dosage , Benzodiazepines/chemistry , Dose-Response Relationship, Drug , Models, Animal , Molecular Structure , Olanzapine , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thymine/administration & dosage , Thymine/chemistry , Thymine/pharmacologyABSTRACT
Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Carbolines/therapeutic use , Estrogen Receptor Antagonists/therapeutic use , Estrogen Receptor alpha/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Carbolines/chemistry , Carbolines/pharmacokinetics , Dogs , Estrogen Receptor Antagonists/chemistry , Estrogen Receptor Antagonists/pharmacokinetics , Female , Humans , MCF-7 Cells , Macaca fascicularis , Mice , Molecular Structure , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding K(i) 0.7 nM; GR reporter gene functional K(i) 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.
Subject(s)
Isoquinolines/chemistry , Isoquinolines/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Dogs , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Kinetics , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Rats , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, we hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, we synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Our data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.
Subject(s)
Asthma/drug therapy , Asthma/enzymology , Janus Kinase 1/antagonists & inhibitors , Lung/enzymology , Protein Kinase Inhibitors/therapeutic use , Administration, Inhalation , Allergens , Animals , Asthma/pathology , Dexamethasone/pharmacology , Dexamethasone/therapeutic use , Disease Models, Animal , Eosinophils/drug effects , Eosinophils/metabolism , Eosinophils/pathology , Guinea Pigs , Inflammation/pathology , Janus Kinase 1/metabolism , Lung/drug effects , Lung/pathology , Ovalbumin , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Signal Transduction , Treatment OutcomeABSTRACT
[reaction: see text] A new method for the solid-phase synthesis of cyanamides is described. The attachment of a secondary amine to solid support is accomplished using Merrifield resin. After functionalization, cleavage is readily achieved with cyanogen bromide to afford the desired cyanamide.
Subject(s)
Cysteine Proteinase Inhibitors/chemical synthesis , Nitriles/chemical synthesis , Pyrrolidines/chemical synthesis , Catalysis , Cyanogen Bromide , Cysteine Proteinase Inhibitors/pharmacology , Indicators and ReagentsABSTRACT
BACKGROUND: The proven efficacy of several anti-cholinergics and beta(2)-agonists and their combinations in both chronic obstructive pulmonary disease (COPD) and asthma strongly validates this therapeutic approach. As a consequence and although technically challenging, over the past 4 years there has been a growing interest in the generation of dual pharmacology Muscarinic-receptor antagonists-beta(2)-adrenergic receptor agonists (MABAs) for the treatment of COPD. OBJECTIVE/METHODS: This article surveys and reviews the research activity in the MABA area to the end of August 2008. RESULTS/CONCLUSION: Although the activity in this field seems to still be limited to a few companies, significant progress in the discovery of a MABA has been achieved with the progression of at least one candidate (GSK-961081) to the clinic.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Bronchodilator Agents/pharmacology , Muscarinic Antagonists/pharmacology , Adrenergic beta-Agonists/therapeutic use , Animals , Asthma/drug therapy , Bronchodilator Agents/therapeutic use , Drug Design , Humans , Muscarinic Antagonists/therapeutic use , Patents as Topic , Pulmonary Disease, Chronic Obstructive/drug therapyABSTRACT
A virtual screening approach comprising a 3-D similarity search based on known GR modulators was used to identify a novel series of non-steroidal glucocorticoid receptor (GR) antagonists. Optimization of the initial hit to provide potent compounds which exhibit good selectivity against other steroidal nuclear hormone receptors is described.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antidepressive Agents/chemical synthesis , Glucocorticoids/chemistry , Receptors, Glucocorticoid/metabolism , Animals , Antidepressive Agents/pharmacology , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Humans , Kinetics , Models, Chemical , Molecular Conformation , Rats , Receptors, Steroid/metabolism , Structure-Activity RelationshipABSTRACT
The 2-azadecalin ring system was evaluated as a scaffold for the preparation of glucocorticoid receptor (GR) antagonists. High affinity, selective GR antagonists were discovered based on a hypothetical binding mode related to the steroidal GR antagonist RU-43044. 2-Benzenesulfonyl substituted 8a-benzyl-hexahydro-2H-isoquinolin-6-ones exemplified by (R)-37 had low nanomolar affinity for GR with moderate functional activity (200 nM) in a reporter gene assay. These compounds were devoid of affinity for other steroidal receptors (ER, AR, MR, and PR). Analogues based on an alternative putative binding mode (CP-like) were found to be inactive.
Subject(s)
Benzene/chemistry , Hydrogen/chemistry , Isoquinolines/chemistry , Isoquinolines/pharmacology , Receptors, Glucocorticoid/antagonists & inhibitors , Sulfur/chemistry , Isoquinolines/chemical synthesis , Molecular Structure , Protein Binding , Receptors, Glucocorticoid/metabolism , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Quinazolines/chemistry , Quinazolines/pharmacology , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Conformation , Quinazolines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II and in vitro inhibitory value for PBMC proliferation are discussed.